Application of tumor pH/hypoxia-responsive nanoparticles for combined photodynamic therapy and hypoxia-activated chemotherapy

Introduction: Cancer selectivity, including targeted internalization and accelerated drug release in tumor cells, remains a major challenge for designing novel stimuli-responsive nanocarriers to promote therapeutic efficacy. The hypoxic microenvironment created by photodynamic therapy (PDT) is believed to play a critical role in chemoresistance. Methods: We construct dual-responsive carriers ((NPCT)-N-DA) that encapsulate the photosensitizer chlorin e6 (Ce6) and hypoxia-activated prodrug tirapazamine (TPZ) to enable efficient PDT and PDT-boosted hypoxia-activated chemotherapy. Results and discussion: Due to TAT masking, (NPCT)-N-DA prolonged payload circulation in the bloodstream, and selective tumor cell uptake occurred via acidity-triggered TAT presentation. PDT was performed with a spatially controlled 660-nm laser to enable precise cell killing and exacerbate hypoxia. Hypoxia-responsive conversion of the hydrophobic NI moiety led to the disassembly of (NPCT)-N-DA, facilitating TPZ release. TPZ was reduced to cytotoxic radicals under hypoxic conditions, contributing to the chemotherapeutic cascade. This work offers a sophisticated strategy for programmed chemo-PDT.